F O C U S O N P A R K I N S O N S D I S E A S E

7 VOL UME 2 2 - I S S UE 1 - 2 0 1 1
ORI GI NAL CONTRI BUTI ON
L E VODOPA THE HI S TORY
T
he racemate dl-dopa was synthesized for the frst
time in 1911 by a Polish biochemist, Casimir Funk
(Figure 1).
1
In 1913 Marcus Guggenheim (Figure 2),
a biochemist working for the company Hoffmann-La Roche
in Basel, isolated the enantiomer levodopa (l-dopa) from the
broad bean plant Vicia faba.
2
A self-experiment with l-dopa
2.5 g taken orally did not show any other effect than nausea and
vomiting, and subsequent pharmacological studies by himself
and others did not indicate any pharmacological effect. More
than 40 years later Arvid Carlsson, a Swedish scientist, studied
the possible role of l-dopa (l-3,4-dihydroxyphenylalanine)
and 5-hydroxytryptophan as reserpine antagonists. Reserpine
was introduced into clinical medicine in the mid-1950s as
the first selective treatment
for schizophrenia. Carlsson
injected reserpine into mice,
inducing marked tranquillization
and complete ptosis of the
eyelid. 5-Hydroxytryptophan,
the precursor of serotonin,
was unable to antagonize the
tranquillizing action of reserpine
and ptosis persisted, but after the
injection of l-dopa the animals resumed normal behaviour
for some time. He postulated that the effect of l-dopa was
probably due to an amine metabolite.
3
By 1939, Blaschko
4
and Holtz
5
had postulated the
pathway of catecholamine synthesis in the body (l-tyrosine
l-dopa dopamine noradrenaline adrenaline).
After having improved the assay by combining ion-exchange
chromatography with a fuorimetric method, they were able
to measure dopamine (3-hydroxytyramine) in tissues shortly
afterwards. In the following year, Carlsson published his
famous paper On the presence of 3-hydroxytyramine in the
brain,
6
and Bertler and Rosengren reported the localization
of dopamine in the basal ganglia of the dog
7
and showed that
in the human brain most of the dopamine is concentrated in
the basal ganglia.
8
Based on these discoveries, the Austrian-Polish-
Ukrainian researcher Oleh Hornykiewicz decided to
measure post-mortem dopamine levels in brains from
patients with Parkinsons disease (PD), obtained from
the Austrian neurologist Walter Birkmayer. Ehringer and
Hornykiewicz discovered that the striatum in these brains
was almost devoid of dopamine.
9
In 1961, Birkmayer
received a small amount of l-dopa from Hornykiewicz and
injected it intravenously into 20 patients with severe PD.
He documented in a flm that these patients resumed normal
movements for a few hours
10,11
and presented the results at
the Medical Society in Vienna.
In the same year, in Canada, Andr Barbeau published
a paper showing that patients with PD excrete much lower
quantities of dopamine in their urine compared with those
without PD and that single doses of l-dopa given to PD
patients reduce rigidity. The l-dopa effect was increased and
prolonged by the addition of a monoamine oxidase (MAO)
inhibitor.
12,13
Additional clinical observations with oral l-dopa, usually
at dosages below 1.5 g/day, were rather controversial.
14,15

In 1966, Birkmayer combined l-dopa with benserazide,
a decarboxylase inhibitor (DCI) being tested at that time
as an antihypertensive agent, and gave the combination
to a few hypertensive PD patients as proposed by
Pletscher. Pletschers hypothesis was that preventing the
decarboxylation of l-dopa would inhibit the formation of
dopamine and thereby inhibit the therapeutic action of
l-dopa.
16,17
A few months later Birkmayer came back with
absolutely unexpected results: not only did benserazide fail
to inactivate l-dopa in PD patients, but it actually made
L- DOPA: THE DRUG THAT
CHANGED THE HI STORY OF
PARKI NSON S DI SEASE
Gianni Pezzoli*, Michela Zini*, and Roman Amrein
* I CP Pa r ki ns o n I ns t i t ut e , Mi l a n, I t a l y
La nd ha u s we g 3 1 , CH 41 26 Be t t i ng e n Ba s e l , Swi t z e r l a nd
Figure 1. Commemorative
postage stamp in honour of
C. Funk.
F O C U S O N P A R K I N S O N S D I S E A S E
8 VOL UME 2 2 - I S S UE 1 - 2 0 1 1
it much more effective. Within months the reason for this
unexpected result was clarifed: benserazide does not penetrate
the bloodbrain barrier. It therefore reduces the metabolism of
l-dopa only in the periphery, with the consequence that more
l-dopa reaches the brain, where it can be transformed by the
decarboxylase to dopamine, for a longer period of time.
18,19
A Greek-American neurologist, George Constantin
Cotzias, has the merit of having been the frst physician to
treat PD patients with high doses of l-dopa for a prolonged
period of time. He started by giving 18 patients an oral
formulation of dl-dopa for 157 + 61 days at daily doses
of 9.7 + 4.1 g/day (maximum 16 g/day). Most patients
showed either complete sustained disappearance or
marked amelioration of their individual manifestation of
parkinsonism. Nausea, feeling faint, and vomiting were
common side-effects with increments larger than 0.5
g/dose.
20
In 1968, Cotzias published a letter
21
in which he
claimed to have abandoned racemic dl-dopa and to have 21
unpublished observations with l-dopa taken at daily doses
of up to 8 g: The evidence so far suggests that l-dopa is a
more effective agent than dl-dopa. In the following year he
published the results from 28 chronically treated patients:
22

l-dopa induced at least partial improvement of some
manifestations in a series of 28 patients with parkinsonism.
Nausea and vomiting were the most common side-effects
and required slow, gradual administration of l-dopa, or the
co-administration of protein-containing foods, or both. In
the same publication he reported that the use of a peripheral
dopa-decarboxylase inhibitor (carbidopa) diminished the
therapeutic dose of l-dopa and eliminated anorexia and
nausea in one case.
Roche was the frst company to introduce l-dopa
(Larodopa

) onto the market in 1970.

23
The combination of
l-dopa plus benserazide (Madopar

) reached the market in

1973 and was followed by the combination of l-dopa plus
carbidopa (Sinemet

, DuPont) in 1974. Since then, l-dopa

in fxed combination with a DCI (Madopar

or Sinemet

)
has been the mainstay of antiparkinson treatment and is used
daily by millions of patients worldwide.
L - DOPA P HARMACOKI NE TI CS AND
ME TABOL I S M
l-dopa is mainly absorbed from the upper tract of the
small intestine, in the duodenum and jejunum, by active
long-chain neutral amino acid transporters.
2427
These
transporters are used by all long-chain neutral amino acids
and are subject to kinetic saturation.
28
Consequently, a diet
rich in neutral amino acids reduces the uptake of l-dopa
in the bowel. Other factors, such as the rate of gastric
emptying and the pH of gastric juice, have an impact on
the rate and extent of l-dopa absorption.
24,29
l-dopa already
undergoes important intestinal metabolism during intestinal
Figure 2. M. Guggenheim (left), 1911. Director of Pharmacology, Roche Grenzach.
F O C U S O N P A R K I N S O N S D I S E A S E
9 VOL UME 2 2 - I S S UE 1 - 2 0 1 1
absorption, since the mucosa of the small intestine contains
decarboxylase in high concentrations. Over half of an oral
dose of l-dopa is decarboxylated to dopamine during the frst
passage through the gut wall of the dog.
30,31
In the presence
of a DCI, local metabolism is considerably reduced and the
bioavailable amount is increased.
28
Metabolism during the
frst passage through the liver is an additional cause of the
low bioavailability of l-dopa: once l-dopa has reached the
plasma it is quickly metabolized by decarboxylase, which
is found in large quantities in the liver, kidney, and heart.
This results in low bioavailability and a short half-life (about
90 minutes).
32
Bioavailability is approximately 35%,
33
and
probably less than 1% passes into the brain if l-dopa is
ingested without an additional DCI. Formation of dopamine
by aromatic amino acid decarboxylases (AADCs) is by far
the most important metabolic pathway. The formation
of 3-O-methyldopa (3-OMD) by the enzyme catechol-
O-methyltransferase (COMT) becomes of importance if
AADC is inhibited by a DCI. Transamination by tyrosine
aminotransferase and oxidation are of lesser importance.
Peripheral dopamine cannot penetrate the bloodbrain
barrier, but produces undesirable peripheral effects, mainly
nausea and vomiting, and, at higher concentrations, also
hypotension and cardiac arrhythmias. The half-life of
3-OMD is about 1215 hours,
34,35
and the substance is
devoid of major peripheral pharmacological effects in PD
patients.
36,37
Peripheral l-dopa reaches the bloodbrain
barrier via the bloodstream and passes through it.
In healthy people, l-dopa is synthesized in the cytoplasm
of dopaminergic neurons in the substantia nigra, after which
it is decarboxylated to dopamine by intracellular AADC.
Dopamine becomes protonated and accumulates rapidly
in the synaptic vesicles of the nerve terminals. Dopamine
concentration in the vesicles can exceed 135,000 times the
concentration in the cytoplasm.
38,39
Overt parkinsonism does not present until approximately
5070% of striatal dopamine loss has occurred and cell death
of dopaminergic cells in the substantia nigra is extensive
due to the progression of the disease.
40
Exogenous l-dopa
enters the residual dopaminergic cells, is decarboxylated
there to dopamine, and stored in the synaptic vesicles;
however, the capacity of the vesicles for both processes is
insuffcient to restore the missing dopamine completely. In
PD, nigrostriatal denervation is associated with upregulation
of postsynaptic dopamine type 2 receptors. It has been
suggested that receptor upregulation, together with the
pulsatile stimulation induced by exogenous dopamine, is
responsible for the narrowing of the therapeutic window
associated with the development of motor side-effects, such
as motor fuctuations and dyskinesias.
41
Unfortunately, as the
disease progresses, increasingly more dopaminergic terminals
are destroyed and the capacity to store dopamine in axonal
terminals diminishes. Consequently, the therapeutic effect
of l-dopa becomes increasingly dependent on its plasma
levels. This condition promotes the development of motor
fuctuations and dyskinesias.
E VOL UTI ON OF ORAL L E VODOPA
THE RAP Y
Ideally, oral l-dopa should be completely absorbed and not
undergo metabolic degradation until it has passed the blood
brain barrier. The most important step to reach this goal was
made when l-dopa was combined with a DCI, which reduces
the quantity of l-dopa required by about 80%, therefore
improving associated peripheral side-effects. Intake on an
empty stomach, restriction of animal protein, and a protein
redistribution diet are highly recommended.
42
Madopar

/
Sinemet

are taken on an empty stomach to achieve a

rapid onset of effect, and together with food to achieve
protracted absorption with reduced effects. With the l-dopa/
DCI combinations the problems of low bioavailability and
peripheral dopamine formation are notably reduced, but the
problem persists of pulsatile l-dopa plasma concentrations
as a consequence of rapid absorption and short elimination
half-life. Controlled-release formulations, such as Sinemet
CR

or Madopar HBS

, prolong the absorption time by

several hours, smoothing out fuctuations in plasma profles,
but at the price of a reduction in bioavailability and,
consequently, in effcacy. The slow-release formulations of
l-dopa have never fully satisfed the needs of neurologists
and patients, as they are unable to control motor fuctuations
completely. It is our experience that in advanced PD with
severe motor fuctuations intermittent dosing of immediate-
release formulations throughout the day at short intervals is
to be preferred over the use of slow-release formulations for
the stabilization of motor performance.
The latest progress in improving the effcacy of oral l-dopa
was made with the introduction of selective and reversible
COMT inhibitors (COMT-Is). Tolcapone, a peripherally
and centrally active COMT-I, was introduced in 1997 by
Roche (Tasmar

), followed a year later by a peripherally

active COMT-I, entacapone (Comtess

, Orion; Comtan

,
Novartis). When COMT-Is are taken in conjunction with
l-dopa/DCI the plasma half-life of l-dopa increases by
approximately 50% and its bioavailability is increased about
2-fold, but its maximum concentration does not increase
and the 3-OMD concentration decreases.
43,44
Tolcapone and
entacapone were both investigated in 5 placebo-controlled
clinical trials in advanced PD. Tolcapone decreased off
time by 1.6 to 3.3 hours and entacapone decreased off
time by 0.9 to 1.3 hours. l-dopa dose was decreased by
80 mg/day to 251 mg/day with tolcapone, and by 19 mg/day
to 100 mg/day with entacapone.
45
In 2 direct comparator
studies, tolcapone was superior to entacapone in increasing
10 VOL UME 2 2 - I S S UE 1 - 2 0 1 1
F O C U S O N P A R K I N S O N S D I S E A S E
on time.
46,47
Hepatic toxicity in 4 tolcapone-treated
patients and the death of 3 patients of 60,000 patients
treated in 1998
48
led to severe restrictions of its use or
withdrawal from the market in some countries. The triple
fxed combination of l-dopa, carbidopa, and entacapone
(Stalevo

, Novartis) was introduced in 2003 and has become

standard therapy for PD patients with motor fuctuations.
49
A further option in advanced PD with severe fuctuations
is continuous intraduodenal l-dopa infusion (Duodopa

,
Solvay) by a gastroduodenal catheter introduced by
percutaneous endoscopic gastrostomy. This formulation
improves daily on time, symptom control, and quality of
life, but is associated with serious technical complications,
such as intestinal infections, torsions with bowel obstruction,
and digestive endoscopy to replace lost or congested
gastroduodenal tubes. It is also very expensive.
5052
The
conclusion is that Continuous infusion of dopaminergic
therapies is impractical for the routine treatment of large
numbers of patients.
53
Efforts to formulate l-dopa/DCI in patches for
transdermal release or for nasal administration by puffs/
aerosols have already failed in early preclinical studies, and
pulmonary delivery systems and the use of prodrugs as a
delivery vehicle for l-dopa have not shown advantages over
standard formulations in clinical trials.
5457
Today, a number of antiparkinson agents are available
that are complementary to l-dopa, these are mainly dopamine
agonists and the MAO-B inhibitors selegiline and rasagiline.
None of them, given alone, are as effective as l-dopa. The
problems associated with l-dopa are not related to effcacy,
but to the serious long-term untoward effects, which develop
after a few years of chronic treatment in most patients: motor
fuctuations and dyskinesias. Dyskinesias develop progressively
over time, depending also on the dosage given. About 40% of
PD patients are adversely affected by dyskinesias within 46
years of initiation of l-dopa treatment.
58
Dyskinesias often
become disabling during long-term treatment, as patients
depend more and more on exogenous l-dopa.
In recent years, the importance of non-motor symptoms
induced by dopaminergic treatment has been acknowledged,
including psychoses
59
and impulse control disorders.
60
The
appearance of these disorders reduces the use of l-dopa.
However, the introduction of atypical antipsychotic agents
that do not have untoward effects on motor function has
reduced the number of patients in whom psychosis becomes
an absolute contraindication for further l-dopa therapy.
59
L - DOPA THE F UTURE
Basic research is investigating two major directions to
replace symptomatic therapy with curative therapy, namely
neuroprotection and replacement of diseased dopaminergic
neurons with new ones.
Neuroprotection aims at detecting PD at an early stage,
long before the frst clinical manifestations, and at slowing
down the degenerative process before it has caused major
damage. Unfortunately, a biological marker for screening
purposes is not available and the cause of PD remains
elusive in more than 90% of cases. These are major
handicaps for systematic research.
The replacement of diseased dopaminergic neurons has
been unsuccessfully attempted in the past with autologous
adrenal gland adrenergic cells and embryonic dopaminergic
neurons. Transplantation of the former appeared to provide
some symptomatic beneft, but had a high morbidity rate.
6168

Transplantation of the latter provided modest benefts in
younger patients and produced severe dyskinesias refractory to
treatment.
6972
Current attempts with autologous stem cells derived
from bone marrow might be able to turn the clock back,
returning the patient to the early stages of the disease
according to preliminary observations.
73
At such stages,
l-dopa provides excellent symptom control without motor
fuctuations or dyskinesias, which are mainly the result of
progression of the disease and the use of high dosages.
Thus, the introduction of novel stem cell or
neuroprotective therapy would not replace l-dopa therapy,
but rather be complementary therapy that restores the
effcacy and tolerability of the drug.
CONCL US I ON
In conclusion, l-dopa combined with a DCI (Madopar

,
Sinemet

, Stalevo

, and generics) has been available for

nearly 40 years. Its discovery was a radical turning point in
the management of PD and, to date, it remains the standard
reference for any kind of treatment to be assessed for use in
PD. It is highly likely that l-dopa will continue to play an
important role in the management of PD in the future, even
after the introduction of novel therapies such as stem cell
transplantation or neuroprotective therapy.
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